tbuckley/cabot-search huggingface dataset:
Intratumoral administration of CD1c (BDCA-1)<sup>+</sup> and CD141 (BDCA-3)<sup>+</sup> myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial
Authors: Julia Katharina Schwarze, Jens Tijtgat, Gil Awada, Louise Cras, Angela Vasaturo, Christopher Bagnall, Ramses Forsyth, Inès Dufait, Sandra Tuyaerts, Ivan Van Riet, Bart Neyns
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces immunogenic cell death, thereby providing maturation signals and enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1) + / CD141 (BDCA-3) + myDCs, in order to reinvigorate the cancer-immunity cycle. Methods In this phase I trial, patients with advanced melanoma who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastases with T-VEC on day 1 followed by IT injection of CD1c (BDCA-1) + myDCs +/- CD141 (BDCA-3) + myDCs on day 2. T-VEC injections were repeated on day 21 and every 14 days thereafter. The number of IT administered CD1c (BDCA-1) + myDCs was escalated from 0.5×10 6 , to 1×10 6 , to a maximum of 10×10 6 cells in three sequential cohorts. In cohort 4, all isolated CD1c (BDCA-1) + / CD141 (BDCA-3) + myDCs were used for IT injection. Primary objectives were safety and feasibility. Repetitive biopsies of treated lesions were performed. Results In total, 13 patients were enrolled (cohort 1 n=2; cohort 2 n=2; cohort 3 n=3; cohort 4 n=6). Patients received a median of 6 (range 3–8) T-VEC injections. The treatment was safe with most frequent adverse events being fatigue (n=11 (85%)), fever (n=8 (62%)), and chills/influenza-like symptoms (n=6 (46%)). Nine (69%) and four patients (31%), respectively, experienced pain or redness at the injection-site. Clinical responses were documented in injected and non-injected lesions. Two patients (cohort 3) who previously progressed on anti-PD-1 therapy (and one patient also on anti-CTLA-4 therapy) developed a durable, pathologically confirmed complete response that is ongoing at 33 and 35 months following initiation of study treatment. One additional patient treated (cohort 4) had an unconfirmed partial response as best response; two additional patients had a mixed response (with durable complete responses of some injected and non-injected lesions). On-treatment biopsies revealed a strong infiltration by inflammatory cells in regressing lesions. Conclusions IT coinjection of autologous CD1c (BDCA-1) + +/- CD141 (BDCA-3) + myDCs with T-VEC is feasible, tolerable and resulted in encouraging early signs of antitumor activity in immune checkpoint inhibitor-refractory melanoma patients. Trial registration number NCT03747744 .
Inclusion of persons with disability in sport: part 2 – best practices and policy recommendations from Qatar
Authors: Josélia Neves, Sanaa Taha Al-Harahsheh, Kamilla Swart, Sabika Shaban, Ali Hudaib
Journal: British Journal of Sports Medicine (2022)

The role of noninvasive positive pressure ventilation (NIPPV) in adult respiratory distress syndrome (ARDS) is controversial, in contrast to its well established benefits in other types of respiratory failure, especially acute exacerbations of chronic obstructive pulmonary disease and cardiogenic pulmonary oedema. We report a case of ARDS caused by <i>Mycoplasma pneumoniae</i> in a 70 year old man, treated with NIPPV in addition to standard medical therapy and analyse current evidence regarding the role of NIPPV in patients with ARDS.
Comparative effectiveness of exercise, antidepressants and their combination in treating non-severe depression: a systematic review and network meta-analysis of randomised controlled trials
Authors: Francesco Recchia, Chit K Leung, Edwin C Chin, Daniel Y Fong, David Montero, Calvin P Cheng, Suk Yu Yau, Parco M Siu
Journal: British Journal of Sports Medicine (2022)

Objective To assess the comparative effectiveness of exercise, antidepressants and their combination for alleviating depressive symptoms in adults with non-severe depression. Design Systematic review and network meta-analysis. Data sources Embase, MEDLINE, PsycINFO, Cochrane Library, Web of Science, Scopus and SportDiscus. Eligibility criteria Randomised controlled trials (1990–present) that examined the effectiveness of an exercise, antidepressant or combination intervention against either treatment alone or a control/placebo condition in adults with non-severe depression. Study selection and analysis Risk of bias, indirectness and the overall confidence in the network were assessed by two independent investigators. A frequentist network meta-analysis was performed to examine postintervention differences in depressive symptom severity between groups. Intervention drop-out was assessed as a measure of treatment acceptability. Results Twenty-one randomised controlled trials (n=2551) with 25 comparisons were included in the network. There were no differences in treatment effectiveness among the three main interventions (exercise vs antidepressants: standardised mean differences, SMD, −0.12; 95% CI −0.33 to 0.10, combination versus exercise: SMD, 0.00; 95% CI −0.33 to 0.33, combination vs antidepressants: SMD, −0.12; 95% CI −0.40 to 0.16), although all treatments were more beneficial than controls. Exercise interventions had higher drop-out rates than antidepressant interventions (risk ratio 1.31; 95% CI 1.09 to 1.57). Heterogeneity in the network was moderate (τ 2 =0.03; I 2 =46%). Conclusions The results suggest no difference between exercise and pharmacological interventions in reducing depressive symptoms in adults with non-severe depression. These findings support the adoption of exercise as an alternative or adjuvant treatment for non-severe depression in adults. Systematic review registration PROSPERO CRD4202122656.
Large-depth three-photon fluorescence microscopy imaging of cortical microvasculature on nonhuman primates with bright AIE probe In vivo
Authors: Hequn Zhang, Peng Fu, Yin Liu, Zheng Zheng, Liang Zhu, Mengqi Wang, Marwan Abdellah, Mubin He, Jun Qian, Anna Wang Roe, Wang Xi
Journal: Biomaterials (2022)

Multiphoton microscopy has been a powerful tool in brain research, three-photon fluorescence microscopy is increasingly becoming an emerging technique for neurological research of the cortex in depth. Nonhuman primates play important roles in the study of brain science because of their neural and vascular similarity to humans. However, there are few research results of three-photon fluorescence microscopy on the brain of nonhuman primates due to the lack of optimized imaging systems and excellent fluorescent probes. Here we introduced a bright aggregation-induced emission (AIE) probe with excellent three-photon fluorescence efficiency as well as facile synthesis process and we validated its biocompatibility in the macaque monkey. We achieved a large-depth vascular imaging of approximately 1 mm in the cerebral cortex of macaque monkey with our lab-modified three-photon fluorescence microscopy system and the AIE probe. Functional measurement of blood velocity in deep cortex capillaries was also performed. Furthermore, the comparison of cortical deep vascular structure parameters across species was presented on the monkey and mouse cortex. This work is the first in vivo three-photon fluorescence microscopic imaging research on the macaque monkey cortex reaching the imaging depth of ∼1 mm with the bright AIE probe. The results demonstrate the potential of three-photon microscopy as primate-compatible method for imaging fine vascular networks and will advance our understanding of vascular function in normal and disease in humans.
SARS-CoV-2 Omicron variant infection was associated with higher morbidity in patients with cirrhosis
Authors: Anand V Kulkarni, Chandan S Metage, Baqar Ali Gora, Sowmya Tirumalle, Kalyan Rakam, Anveshi Satyavadi, Mithun Sharma, Sameer Shaik, Deepika Gujjarlapudi, Padaki Nagaraja Rao, D Nageshwar Reddy
Journal: Gut (2022)

<h3>Abstract</h3> Designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tools are extensively used to manipulate neuronal activity in a cell type-specific manner. Whole-cell patch-clamp recordings indicate membrane depolarization, coupled with increased neuronal firing rate, following administration of the DREADD ligand, clozapine-N-oxide (CNO) to activate the Gq-coupled DREADD, hM3Dq. Although hM3Dq has been used to enhance neuronal firing in order to manipulate diverse behaviors, often within 30 min to 1 h after CNO administration, the physiological effects on excitatory neurotransmission remain poorly understood. We investigated the influence of CNO-mediated hM3Dq DREADD activation on distinct aspects of hippocampal excitatory neurotransmission at the Schaffer collateral-CA1 synapse in hippocampal slices derived from mice expressing hM3Dq in Ca<sup>2+</sup>/calmodulin-dependent protein kinase α (CamKIIα)-positive excitatory neurons. Our results indicate a clear dose-dependent effect on field EPSP (fEPSP) slope, with no change noted at the lower dose of CNO (1 μM) and a significant, long-term decline in fEPSP slope observed at higher doses (5–20 μM). Further, we noted a robust θ burst stimulus (TBS) induced long-term potentiation (LTP) in the presence of the lower CNO (1 μM) dose, which was significantly attenuated at the higher CNO (20 μM) dose. Whole-cell patch-clamp recording revealed both complex dose-dependent regulation of excitability, and spontaneous and evoked activity of CA1 pyramidal neurons in response to hM3Dq activation across CNO concentrations. Our data indicate that CNO-mediated activation of the hM3Dq DREADD results in dose-dependent regulation of excitatory hippocampal neurotransmission and highlight the importance of careful interpretation of behavioral experiments involving chemogenetic manipulation.
Inclusion of persons with disability in sport: part 1 – rights and challenges in Qatar
Authors: Sanaa Taha Al-Harahsheh, Kamilla Swart, Josélia Neves, Sabika Shaban
Journal: British Journal of Sports Medicine (2022)

Although breast cancer is a heterogeneous disease that is challenging to characterize and treat, the recent explosion of genetic and epigenetic research may help improve these endeavors. In the present review, we use genetic diversity to characterize and classify different types of breast cancer. We also discuss genetic and epigenetic changes that are involved in the development of different breast cancer types and examine how these changes affect prognosis. It appears that while a combination of mutations and copy number changes determine the type of breast cancer, epigenetic alterations may be the primary initiators of cancer development. Understanding these critical biomarkers and molecular changes will advance our ability to effectively treat breast cancer. Next, we examine potential drug therapies directed at epigenetic changes, as such epigenetic drug treatments may prove useful for treating patient-specific tumors, breast cancer progenitor cells, and drug-resistant cells. Lastly, we discuss on mechanisms of carcinogenesis, including a novel hypothesis outlining the role of epigenetics in the development of cancer progenitor cells and metastasis. Overall, breast cancer subtypes may have a similar epigenetic signal that promotes cancer development, and treatment may be most effective if both epigenetic and genetic differences are targeted.
Mass cytometry-based peripheral blood analysis as a novel tool for early detection of solid tumours: a multicentre study
Authors: Qi Zhang, Mao Ye, Cheng Lin, Manyi Hu, Yangyang Wang, Yu Lou, Quanming Kong, Jungang Zhang, Junjian Li, Yuhua Zhang, Tianxing Yang, Xu Sun, Weiyun Yao, Yongfei Hua, Haifeng Huang, Minghui Xu, Xiaoguang Wang, Xin Yu, Weifeng Tao, Runtian Liu, Yuming Gao, Tian Wang, Jianing Wang, Xiaobao Wei, Jiangchao Wu, Zhengping Yu, Chengwu Zhang, Chaohui Yu, Xueli Bai, Tingbo Liang
Journal: Gut (2022)

Early detection of a tumour remains an unmet medical need, and approaches with high sensitivity and specificity are urgently required. Mass cytometry time-of-flight (CyTOF) is a powerful technique to profile immune cells and could be applied to tumour detection. We attempted to establish diagnostic models for hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC).We performed CyTOF analysis for 2348 participants from 15 centres, including 1131 participants with hepatic diseases, 584 participants with pancreatic diseases and 633 healthy volunteers. Diagnostic models were constructed through random forest algorithm and validated in subgroups.We determined the disturbance of systemic immunity caused by HCC and PDAC, and calculated a peripheral blood immune score (PBIScore) based on the constructed model. The PBIScore exhibited good performance in detecting HCC and PDAC, with both sensitivity and specificity being around 80% in the validation cohorts. We further established an integrated PBIScore (iPBIScore) by combining PBIScore and alpha-fetoprotein or carbohydrate antigen 19-9. The iPBIScore for HCC had an area under the curve (AUC) of 0.99, 0.97 and 0.96 in training, internal validation and external validation cohorts, respectively. Similarly, the iPBIScore for PDAC showed an AUC of 0.99, 0.98 and 0.97 in the training, internal validation and external validation cohorts, respectively. In early-stage and tumour-marker-negative patients, our iPBIScore-based models also showed an AUC of 0.95-0.96 and 0.81-0.92, respectively.Our study proved that the alterations of peripheral immune cell subsets could assist tumour detection, and provide a ready-to-use detection model for HCC and PDAC.
Diet fuelling inflammatory bowel diseases: preclinical and clinical concepts
Authors: Timon E Adolph, Jingwan Zhang
Journal: Gut (2022)

The diet and gut microbiota have been extensively interrogated as a fuel for gut inflammation in inflammatory bowel diseases (IBDs) in the last few years. Here, we review how specific nutrients, typically enriched in a Western diet, instigate or deteriorate experimental gut inflammation in a genetically susceptible host and we discuss microbiota-dependent and independent mechanisms. We depict the study landscape of nutritional trials in paediatric and adult IBD and delineate common grounds for dietary advice. Conclusively, the diet reflects a critical rheostat of microbial dysbiosis and gut inflammation in IBD. Dietary restriction by exclusive enteral nutrition, with or without a specific exclusion diet, is effectively treating paediatric Crohn’s disease, while adult IBD trials are less conclusive. Insights into molecular mechanisms of nutritional therapy will change the perception of IBD and will allow us to enter the era of precision nutrition. To achieve this, we discuss the need for carefully designed nutritional trials with scientific rigour comparable to medical trials, which also requires action from stake holders. Establishing evidence-based dietary therapy for IBD does not only hold promise to avoid long-term immunosuppression, but to provide a widely accessible therapy at low cost. Identification of dietary culprits disturbing gut health also bears the potential to prevent IBD and allows informed decision making in food politics.
Training patterns associated with injury in New York City Marathon runners
Authors: Brett G Toresdahl, Jordan D Metzl, James Kinderknecht, Kathryn McElheny, Polly de Mille, Brianna Quijano, Mark A Fontana
Journal: British Journal of Sports Medicine (2022)

Training patterns are commonly implicated in running injuries. The purpose of this study was to measure the incidence of injury and illness among marathon runners and the association of injuries with training patterns and workload.Runners registered for the New York City Marathon were eligible to enrol and prospectively monitored during the 16 weeks before the marathon, divided into 4-week 'training quarters' (TQ) numbered TQ1-TQ4. Training runs were tracked using Strava, a web and mobile platform for tracking exercise. Runners were surveyed at the end of each TQ on injury and illness, and to verify all training runs were recorded. Acute:chronic workload ratio (ACWR) was calculated by dividing the running distance in the past 7 days by the running distance in the past 28 days and analysed using ratio thresholds of 1.3 and 1.5.A total of 735 runners participated, mean age 41.0 (SD 10.7) and 46.0% female. Runners tracked 49 195 training runs. The incidence of injury during training was 40.0% (294/735), and the incidence of injury during or immediately after the marathon was 16.0% (112/699). The incidence of illness during training was 27.2% (200/735). Those reporting an initial injury during TQ3 averaged less distance/week during TQ2 compared with uninjured runners, 27.7 vs 31.9 miles/week (p=0.018). Runners reporting an initial injury during TQ1 had more days when the ACWR during TQ1 was ≥1.5 compared with uninjured runners (injured IQR (0-3) days vs uninjured (0-1) days, p=0.009). Multivariable logistic regression for training injuries found an association with the number of days when the ACWR was ≥1.5 (OR 1.06, 95% CI (1.02 to 1.10), p=0.002).Increases in training volume ≥1.5 ACWR were associated with more injuries among runners training for a marathon. These findings can inform training recommendations and injury prevention programmes for distance runners.
DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling
Authors: Cassandra R. Harapas, Kim S. Robinson, Kenneth Lay, Jasmine Wong, Ricardo Moreno Traspas, Nasrin Nabavizadeh, Annick Rass-Rothschild, Bertrand Boisson, Scott B. Drutman, Pawat Laohamonthonkul, Devon Bonner, Jingwei Rachel Xiong, Mark D. Gorrell, Sophia Davidson, Chien-Hsiung Yu, Mark D. Fleming, Jonas Gudera, Jerry Stein, Miriam Ben-Harosh, Emily Groopman, Akiko Shimamura, Hannah Tamary, Hülya Kayserili, Nevin Hatipoğlu, Jean-Laurent Casanova, Jonathan A. Bernstein, Franklin L. Zhong, Seth L. Masters, Bruno Reversade
Journal: Science Immunology (2022)

Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic
C/EBPβ regulates lipid metabolism and <i>Pparg</i> isoform 2 expression in alveolar macrophages
Authors: Dorothea Dörr, Benedikt Obermayer, January Mikolaj Weiner, Karin Zimmermann, Chiara Anania, Lisa Katharina Wagner, Ekaterini Maria Lyras, Valeriia Sapozhnikova, David Lara-Astiaso, Felipe Prósper, Roland Lang, Darío G. Lupiáñez, Dieter Beule, Uta E. Höpken, Achim Leutz, Alexander Mildner
Journal: Science Immunology (2022)

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by accumulation of surfactant lipoproteins within the lung alveoli. Alveolar macrophages (AMs) are crucial for surfactant clearance, and their differentiation depends on colony-stimulating factor 2 (CSF2), which regulates the establishment of an AM-characteristic gene regulatory network. Here, we report that the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is essential for the development of the AM identity, as demonstrated by transcriptome and chromatin accessibility analysis. Furthermore, C/EBPβ-deficient AMs showed severe defects in proliferation, phagocytosis, and lipid metabolism, collectively resulting in a PAP-like syndrome. Mechanistically, the long C/EBPβ protein variants LAP* and LAP together with CSF2 signaling induced the expression of Pparg isoform 2 but not Pparg isoform 1, a molecular regulatory mechanism that was also observed in other CSF2-primed macrophages. These results uncover C/EBPβ as a key regulator of AM cell fate and shed light on the molecular networks controlling lipid metabolism in macrophages.
Tracing the evolutionary history of blood cells to the unicellular ancestor of animals
Authors: Yosuke Nagahata, Kyoko Masuda, Yuji Nishimura, Tomokatsu Ikawa, Shinpei Kawaoka, Toshio Kitawaki, Yasuhito Nannya, Seishi Ogawa, Hiroshi Suga, Yutaka Satou, Akifumi Takaori-Kondo, Hiroshi Kawamoto
Journal: Blood (2022)

Blood cells are thought to have emerged as phagocytes in the common ancestor of animals followed by the appearance of novel blood cell lineages such as thrombocytes, erythrocytes, and lymphocytes, during evolution. However, this speculation is not based on genetic evidence and it is still possible to argue that phagocytes in different species have different origins. It also remains to be clarified how the initial blood cells evolved; whether ancient animals have solely developed de novo programs for phagocytes or they have inherited a key program from ancestral unicellular organisms. Here, we traced the evolutionary history of blood cells, and cross-species comparison of gene expression profiles revealed that phagocytes in various animal species and Capsaspora (C.) owczarzaki, a unicellular organism, are transcriptionally similar to each other. We also found that both phagocytes and C. owczarzaki share a common phagocytic program, and that CEBPα is the sole transcription factor highly expressed in both phagocytes and C. owczarzaki. We further showed that the function of CEBPα to drive phagocyte program in nonphagocytic blood cells has been conserved in tunicate, sponge, and C. owczarzaki. We finally showed that, in murine hematopoiesis, repression of CEBPα to maintain nonphagocytic lineages is commonly achieved by polycomb complexes. These findings indicate that the initial blood cells emerged inheriting a unicellular organism program driven by CEBPα and that the program has also been seamlessly inherited in phagocytes of various animal species throughout evolution.
A Probody T Cell–Engaging Bispecific Antibody Targeting EGFR and CD3 Inhibits Colon Cancer Growth with Limited Toxicity
Authors: Leila M. Boustany, Sherry L. LaPorte, Laurie Wong, Clayton White, Veena Vinod, Joel Shen, Wendy Yu, David Koditek, Michael B. Winter, Stephen J. Moore, Li Mei, Linnea Diep, Yuanhui Huang, Shouchun Liu, Olga Vasiljeva, Jim West, Jennifer Richardson, Bryan Irving, Marcia Belvin, W. Michael Kavanaugh
Journal: Cancer Research (2022)

Abstract T cell–engaging bispecific antibodies (TCB) are highly potent therapeutics that can recruit and activate cytotoxic T cells to stimulate an antitumor immune response. However, the development of TCBs against solid tumors has been limited by significant on-target toxicity to normal tissues. Probody therapeutics have been developed as a novel class of recombinant, protease-activated antibody prodrugs that are “masked” to reduce antigen binding in healthy tissues but can become conditionally unmasked by proteases that are preferentially active in the tumor microenvironment (TME). Here, we describe the preclinical efficacy and safety of CI107, a Probody TCB targeting EGFR and CD3. In vitro, the protease-activated, unmasked CI107 effectively bound EGFR and CD3 expressed on the surface of cells and induced T-cell activation, cytokine release, and cytotoxicity toward tumor cells. In contrast, dually masked CI107 displayed a &amp;gt;500-fold reduction in antigen binding and &amp;gt;15,000-fold reduction in cytotoxic activity. In vivo, CI107 potently induced dose-dependent tumor regression of established colon cancer xenografts in mice engrafted with human peripheral blood mononuclear cells. Furthermore, the MTD of CI107 in cynomolgus monkeys was more than 60-fold higher than that of the unmasked TCB, and much lower levels of toxicity were observed in animals receiving CI107. Therefore, by localizing activity to the TME and thus limiting toxicity to normal tissues, this Probody TCB demonstrates the potential to expand clinical opportunities for TCBs as effective anticancer therapies for solid tumor indications. Significance: A conditionally active EGFR-CD3 T cell–engaging Probody therapeutic expands the safety window of bispecific antibodies while maintaining efficacy in preclinical solid tumor settings.